The present invention is related to improvements in drug substances, and particularly, in improved dissolution control and dissolution stability through manipulation of morphology.
Co-pending U.S. patent Ser. No. 11/595,379 filed Nov. 20, 2006 entitled “Physical States of a Pharmaceutical Drug Substance” discloses the synthesis, purification and use of imipramine pamoate, the disclosure of which is totally incorporated herein by reference. Co-pending U.S. patent application Ser. No. 11/843,890 filed Aug. 23, 2007 also entitled “Physical States of a Pharmaceutical Drug Substance” discloses the synthesis and isolation of an additional polymorphic form of imipramine pamoate. Co-pending U.S. patent application Ser. No. 11/805,225 filed May 22, 2007 entitled, “Salts of Physiologically Active and Psychoactive Alkaloids and Amines Simultaneously Exhibiting Bioavailability and Abuse Resistance”, the disclosure of which is totally incorporated herein by reference, discloses methodology to employ controlled substances for their intended purpose while inhibiting the behavioral act of drug abuse. Co-pending U.S. patent application Ser. No 11/973,252 filed Oct. 5, 2007 entitled, “Improved Drug Safety With Intrinsic Markers” discloses a method for supplying beneficial controlled substances to the commercial market and to those in need of such materials while inhibiting the potential for illicit purposes, the disclosure of which is totally incorporated herein by reference.
The formulation of active pharmaceutical ingredients (APIs) into drug products exhibiting the desired safety, efficacy and release properties is often an arduous process. A pre-formulation investigation is employed to elucidate the physical behavior of the API, also known as the drug substance, to identify its contribution to the formulated dosage characteristics. This assessment provides the formulating practitioner with information necessary to develop a drug product by providing the basis for eliciting a preferred bio-availability response from the drug substance. In other words, the formulation must account for any desired properties not engineered into the drug substance to impart the desired properties by the selection of appropriate excipients or other methodologies. One aspect of the formulation activity is to identify how to decrease, augment or maintain the physical and chemical properties attributable to the drug substance so as to optimize the overall properties of the drug product. In addition, the formulator, with knowledge of the drug substance's physical (and chemical) properties can begin to address the delivery properties of the dosage presentation with respect to a designed pharmacokinetic (PK) and pharmacodynamic (PD) profile.
What is meant by a drug substance is a molecular entity or compound, also known as an active pharmaceutical ingredient (API) that exhibits biological activity for the purpose of providing human or animal medication to treat disease, pain or any medically diagnosed condition. It is possible for a drug substance to be used in combination with one or more different drug substances to ultimately impart a biological response in humans or animals. A drug substance is typically formulated with other, non-biologically active compounds to provide a means of predictable and quantitative dosage delivery, or perhaps to impart acceptable stability features to the drug product.
What is meant by a drug product is a formulation, mixture or admixture of the drug substance with combinations of excipients, processing aids, buffers and perhaps other inert ingredients that allow delivery of the drug substance by the selected dosage form and administration route to the patient. Various dosage forms include, for example, pills, tablets, capsules, solutions, suspensions, and transdermal patches to name a few. Various routes of administration may include oral, nasal, rectal, vaginal, inhalation or injection along with numerous others. Such routes of administration dosage form descriptions may be found in tablature format in the Red Book, Pharmacy's Fundamental Reference, 2005 Edition, published by Thomson on pages 177 and 178, respectively. The dosage is the actual concentration delivered to the patient, and depending upon many factors and the actual delivery system selected, the dosage may be available for essentially immediate release, release over time, or manipulated by additional means for stimulated release (for example, by irradiation).
For solid oral dose or suspension presentations, and where the drug substance is a solid, a polymorph evaluation must be performed on the API. For drug substances capable of existing in one or more polymorphic forms (and perhaps in an amorphous form), a polymorphic evaluation must be performed to determine the equilibrium solubility profile of each crystalline form and to identify the stability profile of each polymorph. One aspect of the stability profile is to demonstrate the selected polymorph retains its polymorphic characteristic as a function of time, temperature and humidity. If the selected polymorph represents a meta-stable state and upon exposure to time and temperature it converts to a different morphological form, the dosage presentation, i.e. the formulated product, may behave differently from its intended pharmaceutical application.
The United States Food and Drug Administration (FDA) has recognized the necessity to clearly define an API's polymorphic specifications when used in a drug product. In the FDA's Guidance for Industry, ANDAs: Pharmaceutical Solid Polymorphism, the impact of drug bioavailability and bioequivalence are discussed with respect to a drug substance's polymorphic behavior. References abound for the formulating practitioner that teach the advantages of the amorphous state of a drug product for providing enhanced solubility and dissolution rates versus the polymorphic (i.e. crystalline) states of the same compound. For example, in the “Handbook of Pharmaceutical Salts; Properties, Selection and Use” (Wiley-VCH, 2002, p. 49), the amorphous state of a drug substance leads to increased bioavailability compared to a polymorphic form. This behavior is attributed to enhanced solubility and dissolution rate. Similarly in “Polymorphism in Pharmaceutical Solids”, (Marcel Dekker, 1999, p. 281), the polymorphs identified as having comparative less crystalline composition will exhibit higher solubility and dissolve more quickly than more stable polymorphs of the same compound. Polymorphic forms and their comparative aqueous solubility are also discussed in “Drug Bioavailability; Estimation of Solubility, Permeability, Absorption and Bioavailability”, (Wiley-VCH, 2003, p. 218-19). “Drug Bioavailability” states that the highest-melting point polymorph (most stable) exhibits the least solubility, and as a rule, holds for solubility measurements performed at either room temperature or body temperature.
An important issue surrounding the current unprecedented activity in generic drug development is the evaluation of existing pharmaceutical products to identify their polymorphic behavior and to incorporate the correct polymorph (or one with associated bio-equivalence or defined behavior) into a generic commercial offering. Simultaneously, the generic product must exhibit a favorable impurity profile compared to the original, innovator product. Frequently for older drug products, the degree to which the active ingredient may be present in one or more polymorphic forms has not been explored or well characterized (if at all). Different polymorphic forms can radically influence a drug's release properties and result in a dramatically altered pharmacokinetic behavior for the patient.
To demonstrate the preceding assertion, U.S. Pat. No. 3,326,896 [Holstius] is illustrative, and the disclosure is totally incorporated herein by reference. The author discloses three embonic (pamoic acid) addition salts free from unpleasant taste and local anesthetic properties, and useful for the treatment of depression. The addition salt of 5-(3-dimethylaminopropyl)dihydro-5H-dibenz-[b,f]-azepine, (imipramine), was absorbed more slowly than the corresponding hydrochloride salt. Processes for making the embonic acid addition salts in aqueous and organic media were also disclosed. A review of the reported laboratory work reveals an anomalous observation in that the same “melting point” was reported for the pamoate salt of 5-(3-dimethylaminopropyl)-10,11-dihydro-5H-dibenz[b,f]azepine as for 5-(3-methylaminopropyl)-10,11-dihydro-5H-dibenz[b,f]azepine derivative. Both “melting points” were reported as 125-150° C. even though they are different compounds prepared under the same aqueous conditions. Melting ranges of this magnitude are generally associated with the presence of impurities and/or the presence of solvates/hydrates. In connection with the material the authors isolated, no crystalline forms were observed or claimed, and indeed, no attempt was made to characterize crystalline forms through techniques such as microscopy or X-ray powder diffraction patterns. Further, no calorimetry was performed thus clues gleaned from heats of fusion or heats of hydration were not provided. Interestingly, the author claims the embonic acid addition salt of 5-(3-dimethyl-aminopropyl)-10,11-dihydro-5H-dibenz[b,f]azepine, however the salt is not characterized as the 1:1 salt or as the 2:1 salt or some mixture thereof. Perhaps the broad melting point reported in the specification suggests the presence of impurities and/or the presence of unidentified solvates or hydrates.
In addition to the indefinite polymorphic issues associated with the API as described above in Holstius, the impact on the drug's in vivo (rat) behavior yielded a conclusion from the investigators that, “there is a slower rate of absorption of the embonate, but that at 8 hours, the levels attained with the embonate exceed those of the hydrochloride”. It should also be noted here that an embonate is an alternative name for pamoate. Additionally, the investigators evaluated the embonates and analogous hydrochloride salts for toxicity (LD50 comparison of intraperitoneal and peroral administration of each salt type). Here too a “surprising finding” of reduced acute toxicity was observed for the embonates compared with the hydrochlorides. The two findings appear to be in contradiction since the embonates ultimately reached levels exceeding those of the hydrochloride.
A number of drug substance and drug product development, manufacturing, pharmacological performance and stability features must be addressed to adequately commercialize a drug product. In the course of drug product development, a perplexing and paradoxical dilemma occurs when an API exhibits the ability to exist in different polymorphic forms and may through time, and/or temperature and humidity effects, convert to another crystalline form. It is well known that these changes in a defined polymorphic form can lead to significant differences in the physiological response the drug exhibits. At a minimum, the dissolution rates (in vitro or in vivo) are expected to change, and the release properties of the active ingredient from its crystalline matrix or from the formulated drug product are also likely to change. As dissolution, or in vivo solubility changes, the overall bio-availability of the active ingredient may also change. The consequence is that too many variables are introduced to fully or adequately evaluate the drug's beneficial properties.
To provide a step-wise presentation of the necessary activities occurring during drug product development, basic toxicity and pharmacological studies are implemented to evaluate the drug's potential safety and efficacy. Ideally, the drug substance's chemical stability is sufficient so as not to complicate the evaluation through non-metabolic impurity-generating degradation pathways. Equally important is that the drug substance exhibit physical stability throughout the final stages of its manufacture, formulation to a drug product, packaging, storage, distribution and use (e.g. clinical trial testing, etc.). For APIs which may exist in multiple polymorphic forms, this potential for physical (form) transformation has huge technical, medical and financial implications. It is estimated that only one in ten thousand drug candidates are ever commercialized with the vast majority of candidates having early failures (for toxicity, efficacy, safety, etc.). It is unclear if the high failure rate is the result of an improper assessment of the data, or a correct assessment of the results but under false assumptions. In other words, the compound and its formulation did not represent what was actually evaluated. Similarly, the literature contains numerous examples of approved drug products “drifting” to less than effective materials because of polymorphic issues arising and altering the bio-availability domain of the API.
This logic also extends into the actual manufacture of the drug substance. Early in drug substance process development, it may be unknown or poorly understood what process factors influence a drug substance's physical form. Further, little to no expenditure has been allocated to evaluate the substance's propensity for existing in multiple polymorphic forms (including amorphous material). Typically, the business goal is to prepare adequate quantities of API at reasonable purity and to quickly perform a screening evaluation for toxicity and therapeutic effect. The intention of these activities is to quickly ascertain if the intended drug is worthy of the significant financial expenditure to commercialize the product. With favorable toxicity results and a positive indication to expect reasonable therapeutic benefit, a more detailed technical investigation ensues. Again, the literature abounds with post-commercialization polymorphic issues arising and disrupting the expected benefit of a drug product. It is reasonable to conclude that an exhaustive investigation of potential physical forms of drug substances is typically absent from the drug substance development process. Indeed, an “exhaustive investigation” is not practical and inherently requires violating the philosophical principle of proving a negative condition. Simply stated, it is not possible to prove that an API has a fixed number of polymorphic or solvatomorphic forms under all circumstances and conditions.
The practical solution to the polymorphic possibilities associated with a drug substance is to establish stable process conditions which yield a singular and analytically defined physical form of the drug substance. This form is then subjected to challenging environments to which the API may be reasonably exposed during its manufacturing process and subsequent down-stream manipulations (i.e. formulation and tableting/(en)-capsulating, etc.). These tests also may include evaluating the chemical and physical stability of the drug substance. The drug substance is also likely to be tested under routine and accelerated stability storage conditions. Here, the API is packaged and subjected to 25° C./60% relative humidity and 40° C./75% relative humidity conditions. The formulated drug product is also packaged and stored under these conditions to determine its chemical and physical stability also. Accelerated storage stability testing typically occurs for at least three months, and routine stability testing, upon commercialization, may extend for multiple year periods. Obviously, investment in these activities is often restricted until the basic toxicity and therapeutic effect screening has been performed.
The findings from the challenge tests and the stability storage tests for the API can have a number of ramifications. First, the simplest conclusion is presented when the physical and chemical analysis of the API remains unchanged from the time-zero point. All other findings may have varying levels of consequences to the drug development program. To focus on the physical form, if the polymorphic purity changed beyond that attributable to chemical degradation, the resulting polymorphic form may no longer exhibit the therapeutic properties concluded from previous evaluations. The bio-availability of the drug substance is likely altered and few, if any, definitive conclusions can be drawn. This occurrence represents a lost investment, lost time and a return to nearly the beginning of the drug evaluation process.
Clearly, there remains a technical challenge for improving the drug development process to better assure definitive toxicity and therapeutic findings from drug substances capable of exhibiting polymorphism. One approach is to provide stable polymorphic materials early in the drug development process and thereby eliminate multiple inter-related factors in the drug evaluation process. If the various and essential physical and chemical properties (e.g. stable and predictable morphology) of a drug substance could be pre-determined, tailored or engineered to meet or augment the dissolution properties of the drug substance's corresponding mineral acid salt while improving upon the unpredictable features associated with the mineral acid or simple organic acid salts, significant commercial benefit would be realized. Similarly, by intentionally engineering performance features into the drug substance which have traditionally been imparted by formulation of the drug substance by the addition of excipients, the value of the drug substance is enhanced. In effect, the drug substance will also act as a drug delivery vehicle by assuming properties most often associated with formulation techniques, for example, modified release properties.
In an article by Mike Zaworotko, “Crystal Engineering of the Composition of API's: Understanding Polymorphs and Designing Pharmaceutical Co-Crystals”, published in American Pharmaceutical Outsourcing, 5(4), 216, 2004, the author discusses the “growing field of crystal engineering” and its potential impact on “the formulation side of the pharmaceutical industry”. Zaworotko relates polymorphism as a manifestation of supramolecular assemblies that are formed as a result of molecular components within a molecule having a predisposition to align into a greater aggregate. Different polymorphs can then arise from supramolecular isomerism. The article provides an overview analysis of two APIs (Indomethacin® and Tegretol®) possessing molecular constituents which act as supramolecular synthons and impact the polymorphs, solvates and co-crystals available to these compounds. The author identifies that the physical properties desired of an API are critically dependent upon the supramolecular chemistry and ultimately, that those physical properties of greatest importance in a formulated drug product can be obtained (“in principle”) through crystal engineering of the API. Of particular relevance for which API crystal design could add value are on those APIs that exhibit poor solubility or permeability.